Measuring properties of an anatomical body

ABSTRACT

A medical device includes a sensor that is configured to measure a property of an outer layer of an anatomical body surface. The sensor includes a source probe configured stimulate a local surface of the outer layer of an anatomical body surface. The sensor also includes a detector configured to measure a response of the outer layer resulting from the source probe stimulation. A controller coupled to the source probe and the sensor drives the source probe using a tailored stochastic sequence and determines the property of the outer layer using the measured response received from the detector. The sensor can be used with medical devices, such as drug delivery devices including microneedle transport devices and needleless injection devices.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/657,724, filed Sep. 8, 2003, which is a Continuation of U.S.application Ser. No. 10/656,806, filed on Sep. 5, 2003 which claims thebenefit of U.S. Provisional Application Nos. 60/409,090, filed Sep. 6,2002 and 60/424,114, filed Nov. 5, 2002.

The entire teachings of the above applications are incorporated hereinby reference.

BACKGROUND OF THE INVENTION

Injection of a liquid such as a drug into a human patient or anagriculture animal is performed in a number of ways. One of the easiestmethods for drug delivery is through the skin which is the outermostprotective layer of the body. It is composed of the epidermis, includingthe stratum corneum, the stratum granulosum, the stratum spinosum, andthe stratum basale, and the dermis, containing, among other things, thecapillary layer. The stratum corneum is a tough, scaly layer made ofdead cell tissue. It extends around 10-20 microns from the skin surfaceand has no blood supply. Because of the density of this layer of cells,moving compounds across the skin, either into or out of the body, can bedifficult.

The current technology for delivering local pharmaceuticals through theskin includes methods that use needles or other skin piercing devices.Invasive procedures, such as use of needles or lances, effectivelyovercome the barrier function of the stratum corneum. However, thesemethods suffer from several major disadvantages: local skin damage,bleeding, and risk of infection at the injection site, and creation ofcontaminated needles or lances that must be disposed. Further, whenthese devices are used to inject drugs in agriculture animals, theneedles break off from time to time and remain embedded in the animal.

Needleless injection devices have been proposed to overcome the problemsassociated with needles, but the proposed devices present differentproblems. For example, some needleless injection devices rely on springactuators that offer limited control. Others use solenoids, compressedair or hydraulic actuators also offer limited control.

SUMMARY OF THE INVENTION

Skin sensor apparatus and methods described herein use speciallytailored stimulation to effectively measure one or more properties ofthe surface of an anatomical body, such as the compliance gain and/orstiffness of skin.

A medical device includes a sensor configured to measure a property ofan outer layer of an anatomical body surface. The sensor includes asource probe configured stimulate a local surface of the outer layer ofan anatomical body surface. The sensor also includes a detectorconfigured to measure a response of the outer layer resulting from thesource probe stimulation. Further, the device includes a controllercoupled to the sensor. The controller drives the source probe using atailored stochastic sequence. The controller then determines theproperty of the outer layer using the measured response received fromthe detector.

The body surface can be the skin of a subject, or an internal bodysurface. The body surface can be modeled as a second order mechanicalsystem. Further, the property of the outer layer can be determined usingsystem identification techniques.

The source probe can include a voice coil for stimulating the localsurface of the outer layer. For example the voice coil can be coupled tothe outer layer and driven at a frequency to displace the surface. Thedetector measures displacement of the body surface, for example, usingan accelerometer. In one embodiment, the detector includes a lineardifferential variable transducer detecting displacement of the bodysurface. In some embodiments, the detector further includes a straingauge for measuring a static displacement of the body surface.

The medical device can be a drug injection device. The drug injectiondevice is coupled to the sensor and injects a drug into an anatomicalbody in response to the determined property of the outer layer. Forexample, the device can include a servo-controller coupled to a deliverydevice for delivering a pharmaceutical. The servo-controller adjusts thedelivery characteristics of the delivery device based on the surfaceproperties. In one embodiment, the drug injection device is a needlelessinjector.

A device for injecting drug into a biological body includes a druginjector for holding the drug to be delivered to the body. The devicealso includes a skin sensor that measures skin properties of the bodyand a servo-controller coupled to the drug injector and the skin sensor.The servo-controller adjusts the injection pressure of the drug injectorto selectively deliver the drug to the body based on the skinproperties. In some embodiments, the skin sensor measures the propertiesof the body using a tailored stochastic sequence.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1A is a perspective view of a drug delivery device in accordancewith the invention.

FIG. 1B is a side view of the drug delivery device of FIG. 1A.

FIG. 1C is an end view of the drug delivery device taken along the line1C-1C of FIG. 1B.

FIG. 2 is a perspective view of the drug delivery device of FIG. 1A witha controller and energy source.

FIG. 3A is a graph of the time response of a shape memory alloy fiber ofthe drug delivery device of FIG. 1A for a high strain.

FIG. 3B is a graph of the time response of the shape memory alloy fiberof the drug delivery device of FIG. 1A when the fiber is subjected to apotential as a quick pulse.

FIGS. 4A-4C are respectively side, front, and top views of a hand-helddrug delivery device.

FIG. 4D is a perspective view of the drug delivery device shown in FIGS.4A-4C.

FIG. 5A is a cross-sectional view of the drug delivery device takenalong the line 5A-5A of FIG. 1C prior to delivery of a drug.

FIG. 5B is a cross-sectional view of the drug delivery device of FIG. 1Aduring drug delivery.

FIG. 6A is a perspective view of an alternative embodiment of the drugdelivery device in accordance with the invention.

FIG. 6B is a side view of the drug delivery device of FIG. 6A.

FIG. 6C is top view of the drug delivery device taken along the line6C-6C of FIG. 6B.

FIG. 6D is front view of the drug delivery device taken along the line5D-5D of FIG. 6B.

FIG. 7A is a perspective view of a drug vile for the drug deliverydevice of FIG. 6A.

FIG. 7B is a cross-sectional view of the drug vile of FIG. 7A.

FIG. 8 is a perspective view of the drug delivery device of FIG. 6A witha controller and energy source.

FIG. 9A is a cross-sectional view of the drug delivery device takenalong the line 9A-9A of FIG. 6D prior to delivery of a drug.

FIG. 9B is a cross-sectional view of the drug delivery device duringdrug delivery.

FIG. 10 is cross-sectional view of another alternative embodiment of thedrug delivery device in accordance with the invention.

FIG. 11 illustrates the drug delivery device of FIG. 10 with aprotective sterile ribbon in accordance with the invention.

FIGS. 12A and 12B illustrate yet another alternative embodiment of thedrug delivery device in accordance with the invention.

FIG. 13 illustrates the drug delivery device with a sensor used todetect properties of the skin in accordance with the invention.

FIG. 14 is a block diagram of an alternative embodiment of the sensorused to detect properties of the skin in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

Referring to FIGS. 1A-1C, there are shown various views of a drugdelivery device used to inject a liquid formulation of an activeprinciple, for example, a drug, into biological body such as anagriculture animal or human being. The delivery device is generallyidentified as 10 in the illustrated embodiment as well as in otherembodiments described later. The drug is initially contained in achamber 12 (FIG. 5A) and is injected out through an orifice or outputport 14 into the body.

A nozzle is typically used to convey the drug to the skin at therequired speed and diameter to penetrate the skin as required. Thenozzle generally contains a flat surface, such as the head 17 that canbe placed against the skin and an orifice 14. It is the inner diameterof the orifice 14 that controls the diameter of the drug stream.Additionally, the length of an aperture, or tube, defining the orifice14 also controls the injection pressure. In some embodiments, a standardhypodermic needle is cut to a predetermined length and coupled to thehead. One end of the needle is flush, or slightly recessed, with respectto the surface of the head 17 that contacts the skin to avoid puncturingthe skin during use. The internal diameter of the needle (e.g., 100 ÿm)defines the diameter of the aperture, and the length of the needle(e.g., 5 mm) together with the aperture dimension controls the resultinginjection pressure, for a given applicator pressure. In otherembodiments, a hole can be drilled directly into the head 17 to reduceassembly steps. In general, the length of the orifice is selectable, forexample ranging from 500 ÿm to 5 mm, while its diameter can range from80 ÿn to 200 ÿm.

The device 10 includes a guide tube 16 in which a piston 18 ispositioned. An interchangeable head 17 is attached at an enlarged end 19of the tube 16 with a set of screws 21. One end of the piston 18, alongwith the inside of the enlarged end 19 and head 17 define the chamber12, and a push block 22 is attached at the other end of the piston 18.Although the piston 18 forms a clearance seal with the tube 16, a sealring can be placed about the piston 18 to prevent drug from escapingfrom the chamber 12 between the piston 18 and the tube 16. Attached onthe outside of the push block 22 is an electrical contact plate 24.Another contact plate 26 is positioned between the interchangeable head17 and the enlarged end 19.

In some embodiments, the guide tube 16 includes linear bearings toreduce the friction of the piston 18. Preferably, the piston 18 is rigidto avoid buckling under the force exerted by the actuator. Further, thepiston 18 is light weight to reduce its inertia ensuring a rapidacceleration upon activation. In one embodiment, the piston 18 is formedfrom a hollow aluminum rod. Other parts can also be advantageouslyconstructed of light weight materials. For example, the push block 22can be formed from a machinable poly acetal.

In addition to the contact plates 24 and 26, an actuator 28 includes oneto six or more wires 30 positioned about the tube 16 and parallel to oneanother. One end 32 of each wire 30 is attached to the contact plate 24through the push block 22, and another end 34 of the wire 30 is attachedto a respective capstan 36. The capstan 36, and the contact plates 24and 26 are electrically conductive. Hence, the ends 32 and 34 of thewires 30 are electrically connected to each other through the contactplates 24 and 26, respectively. An insulating collar 38 positioned aboutthe guide tube 20 helps guide the wires 30 through the holes 39 betweenthe enlarged region 19 and the push block 22.

To apply the appropriate tension to the wires 30 and to define thevolume of the chamber 12, a coiled spring 37 is positioned about thepiston 18 between the end of the tube 16 and the push block 22, and thecapstans 36 are turned accordingly, much like adjusting the tension inguitar strings. The wires 30 are wrapped around the respective capstans36 one or more times. As such, the strain near the terminal ends 34 ofthe wires 30 attached to the capstans 36 are significantly less than thestrain along the remainder of the length of the wires 30. For example,the strain near the terminal end 34 may be about 1% while that of theremainder of the wire may be about 15%.

The wires 30 can be secured to the contact plate 24 with capstans, aswell. Alternatively, the wires 30 can be attached to one or both contactplates 24 and 26 by other techniques, for example, by electrodepositionas described in U.S. Pat. No. 5,641,391, the entire contents of whichare incorporated herein by reference.

Alternatively, each wire 30 can be twisted with a respectiveelectrically conductive wire made of, for example, copper or iron. Thetwisted segment is then bent back, and partially twisted forming a loop,with the partially twisted segment formed of two strands of the wire 30and two strands of the copper wire. The formed loop can be placed on apin, for example, or it can be fully twisted and then bent back andpartially twisted forming another loop, with the partially twistedsegment formed of four strands of the wire 30 and four strands of thecopper wire. Again, the formed loop can be placed on a pin to secure thewire 30 to the contact plate 24 and/or 26.

More generally, the wires 30 can be formed from a shape memory materialthat changes from a first stable state to a second stable state uponexcitation. For example, the shape memory material can be a shape memorypolymer. Alternatively, or in addition, the shape memory material can bean alloy. In some embodiments, a phase change of the shape memorymaterial occurs when the material is heated. For example, a shape metalalloy can exist with one of two different lattice structures, such thata phase change from one lattice structure to another occurs responsiveto the application and/or removal of thermal energy.

The wires 30 are made of a suitable material that contracts when heatedand can be used as an actuation method. Heating can be accomplished bypassing a current through the wire 30, known as Joule heating. Thus, thecurrent is conducted within the wires 30 after a potential is appliedacross them. A class of materials that contract when a potential isapplied to them includes piezoelectric materials and shape memoryalloys. While piezoelectric crystals contract about 1%, shape memoryalloys are able to contract approximately 15% or more. The largercontraction of shape memory alloys makes them desirable for theillustrated embodiment. Accordingly, the wires 30 are made of shapememory alloy such as, for example, Ni—Ti (also known as Nitinol),available from Shaped Memory Applications Inc., of San Jose, Calif., andfrom Dynalloy Inc. of Costa Mesa, Calif., under the Trade Mark FLEXINOL.When a potential is applied across the wires 30 via the contact plates24 and 26 the wires 30 heat up. As the wires 30 heat up, a phasetransformation of the wire material occurs, namely, the wire changesphase from martensite to austenite. This phase transformation causes thewires 30 to contract such that the piston 18 is pushed towards theorifice 14, thereby forcing the drug from the chamber 12 out the orifice14. Preferably, the shape memory alloy is fast acting to provide asudden force suitable for injecting a drug into a patient's skin withoutusing a needle. A more detailed description of shape memory alloys andtheir use is described in U.S. Pat. No. 5,092,901, the entire contentsof which are incorporated herein by reference.

To use the device 10, the device is connected to a controller 50 with apair of leads 52, and the controller in turn in connected to a capacitorbank 54 with another pair of leads 56, as illustrated in FIG. 2. Thecontroller 50 can be a simple microprocessor, or alternatively apersonal computer with multifunction capabilities. The capacitors of thebank 54 are energized through a power source in the controller 50 or byan external power source. Once energized, the capacitors, under thedirection of the controller 50, discharge to apply a potential acrossthe wires 30 via the plates 24 and 26 through the leads 52. In thismanner, the wires 30 are connected together in a parallel configuration,the supply potential being applied equally across the ends of each ofthe multiple wires 30. In another embodiment, the wires 30 are connectedtogether in a series configuration. Still other arrangements can be usedto apply the potential across the wires 30, for example, as describe inU.S. application Ser. No. 10/200,574 filed Jul. 19, 2002, by Angel andHunter, the entire contents of which are incorporated herein byreference.

Although any capacitor can be used in the bank 54, a super capacitor hasthe advantageous feature of providing a large energy density in a smallphysical size. Hence the capacitors of the bank 54 can be supercapacitors 53 that have a volume from 1.5 ml to 30 ml, preferably 3 ml,and an energy output of 10 J to 1 KJ, preferably 100 J. The currentapplied to the wires 30 is approximately 100 mAmps to 5 Amps, and thevoltage applied to the wires 30 is between about 1 volt to 10 volts. Inone embodiment, the applied current is 1 Amp, and the applied voltage is5 volts. To heat the wires 30 quickly, larger currents of 25 to 100 Ampscan be applied. As fast action is required, the power source must alsobe able to switch large currents with millisecond timing.

The amount of force per area generated by the wires 30 is about 235MN/m². In the illustrated embodiment, the volume of drug initiallycontained in the chamber 12 is about 200 ÿL to 250 ÿL, and the orifice14 has a diameter of between about 50 ÿm to 500 ÿm. In some embodiments,the drug volume is up to 500 ÿL. The drug injection velocity is about150 m/s with a 150 ÿm orifice 14. Generally, an injection velocity of100 m/s or greater is required for successful skin penetration (e.g.,penetrating skin to a depth of 2 mm) in a stream having a diameter of100 ÿm. Advantageously, the stream diameter of the needleless injectorcan be substantially smaller than a typical 24 gauge needle having adiameter of 450 ÿm.

The device 10 has a length, L₁, of approximately 150 mm, and the wires30 contract about 7 mm when a potential is applied across them. Thewires 30 can have circular cross section, in which case each wire 30 hasa diameter of approximately 0.025 mm to 2 mm, preferably 380 ÿm.Alternatively, each fiber can have a flat ribbon shape with a thicknessapproximately in the range 0.025 mm to 0.5 mm and a width ofapproximately 0.75 mm to 10 mm. Other suitable shape memory alloysinclude Ag—Cd, Au—Cd, Au—Cu—Zn, Cu—Al, Cu—Al—N, Cu—Zn, Cu—Zn—Al,Cu—Zn—Ga, Cu—Zn—Si, Cu—Zn—Sn, Fe—Pt, Fe—Ni, In—Cd, In—Ti, and Ti—Nb.

Referring now to FIGS. 3A and 3B, there are shown graphs of the timeresponse of wires 30 made from Ni—Ti. Shown in FIG. 3A is the responseof a wire subjected to a strain of nearly 5%. As can be seen, thecontraction time for this wire is about 10 ms. By way of contrast, FIG.3B illustrates a wire subjected to faster pulse than that applied to thewire of FIG. 3A. With the faster pulse, the fiber experiences a strainof about 1%, with a contraction time of about 1 ms.

In use, the device 10 is typically mounted within an applicator that isheld by an operator. The applicator can be shaped as a pistol, cylinderor any other suitable geometry. An exemplary applicator is shown inFIGS. 4A through 4D. In one embodiment, referring to FIG. 4A, a pistolshaped applicator 400 includes a barrel 405 configured to house thedevice 10. The barrel 405 can be a hollow tube or rectangle having acavity sized to accept the device 10. Referring to FIG. 4B, the barrel405 includes an aperture 420 at one end sized to accept the head 17 ofthe device 10. The head 17 protrudes through the aperture 420 tofacilitate contact with an animal's skin. Further, the applicator 400includes a handle 410 configured to be grasped by an operator. Thehandle 410 is coupled at one end to the barrel 405. Additionally, theapplicator 400 can include a base 415 coupled to another end of thehandle 410. The base 415 can be configured to house other parts of theneedleless injector, such as the power source and/or control unit. Thehandle 410 can be similarly configured (e.g., hollowed out) to alsohouse parts of the needleless injector. Further, the applicator 400 caninclude a switch 420. The switch 420 can be controlled by an operator tooperate the device 10 to initiate an injection and/or a filling of thedevice with a drug.

Referring to FIGS. 5A and 5B, as well as to FIG. 1A, the operatorpositions the applicator to place a surface 60 of the head 17 againstthe skin, S, of the biological body. Prior to the placement of the head17 against the skin, or while the head 17 is positioned against theskin, the capacitor bank 54 is energized as described above. Theoperator then triggers the device 10 through the controller 50 todischarge the capacitor bank 54, thereby applying a potential across thewires 30 which causes them to contract. As the wires 30 contract, theypull the push block 22, which pushes the piston 18 towards the head 17to force the drug, D, from the chamber 12 through the orifice 14 intothe body. The injection pressure can be as low as 1 MPa or lower or ashigh as 300 MPa. For comparison, a minimum local pressure ofapproximately 1.91 MPa is required for piercing skin to a depth of 2 mmusing a 100 ÿm diameter needle After the energy in the capacitor bank isdepleted, the potential across the wires 30 is removed which causes thewires 30 to extend to their original length as the coiled spring 37pushes the push block 22 away from the head 17. The chamber 12 can thenbe refilled if desired with additional drug to be injected into anotherbody or the same body.

Turning now to FIGS. 6A-6D, there are shown various views of analternative embodiment of the drug delivery device 10, where likefeatures are identified by like numerals. Here, the device 10 includestwo base portions 70 and 72. The piston 18 extends through the baseportion 72 and through part of the base portion 70, as shown, forexample, in FIG. 9A. As before, the piston 18 is attached at one end tothe push block 22, which slides back and forth over a surface 76 of thebase portion 72, such that the piston slides back and forth in the baseportions.

Referring also to FIGS. 7A and 7B, a removable and/or disposable vial 80is mounted in the base portion 70. For example, the vial 80 can be screwmounted to the base portion 70. The vial 80 is provided with a nozzle,as described above, at one end defining the orifice 14. The vial 80 alsoincludes a plunger 82 that moves back and forth in the chamber 12defined within the vial 80. The plunger 82 abuts the terminal end 84 ofthe piston 18. As such, as the piston 18 moves towards the orifice 14,drug, D, contained in the chamber 12 is expelled through the orifice 14.In some implementations, the orifice of the drug vial, or the chamber ofthe embodiment of FIG. 1A, is sealed with a suitable material prior touse. The seal may be manually removed, or it may be removed by theinjection pressure of the drug as it ejects from the vial or chamber.

A single length wire 30 is positioned on each side of the base portions70 and 72 and attached at one end to a lead capstan 90 a, wrappedsequentially around intermediate capstans 90 b, 90 c, 90 d, and attachedat the other end to a terminal capstan 90 e. To apply the appropriatetension to the wires 30, the coiled spring 37 is positioned about thepiston 18 between the base portion 72 and the push block 22, and aratchet mechanism 92 is employed to adjust the tension in the wires 30.The capstans 90 a, 90 c, and 90 e are electrically conductive, and arecoupled to respective conductive bars 94 and 96. The capstans 90 b and90 d are also electrically conductive, and are electrically coupled torespective conductive plates 98 and 100. The plates 98 and 100 in turnare electrically connected to each other through the push block 22, butelectrically insulated from the piston 18 and base portion 72. The twobars 94 and 96 are electrically insulated from the base portion 70. Assuch, when a potential is applied across the conductive bars 94 and 96,the potential is also applied across the four segments of each wire 30.

In one implementation, the device 10 of FIG. 6A is connected to thecontroller 50 with the pair of leads 52, and the controller in turn inconnected to the capacitor bank 54 with another pair of leads 56, asillustrated in FIG. 8. As mentioned above, the capacitors of the bank 54are energized through a power source in the controller 50 or by anexternal power source. Once energized, the capacitors, under thedirection of the controller 50, discharge to apply a potential acrossthe wires 30 via the conductive bars 94 and 96 through the leads 52. Thewires 30 heat up and contract such that the piston 18 is pushed towardsthe orifice 14, thereby forcing the drug D from the chamber 12 of thevial 80 out the orifice 14.

Although shown as blocks, the base portions 70 and 72 can have anysuitable geometry which facilitates the use of the device 10 of FIG. 6Ain a particular application. As mentioned before, the device can bemounted within an applicator that is held by an operator.

Referring to FIGS. 9A and 9B, as well as to FIG. 6A, to use the device10, the operator positions the applicator such that a surface 101 of thevial 80 is placed against the skin, S, of the body. Prior to theplacement of the surface 101 against the skin, or while the surface 101is positioned against the skin, the capacitor bank 54 is energized, asdescribed earlier. The operator then triggers the device 10 through thecontroller 50 to discharge the capacitor bank 54, thereby applying apotential across the wires 30 which causes them to contract. As thewires 30 contract, they pull the push block 22 which pushes the piston18, which in turn pushes the plunger 82 towards the orifice 14 to forcethe drug, D, from the chamber 12 through the orifice 14 into the body.After the energy in the capacitor bank is depleted, the potential acrossthe wires 30 is removed which causes the wires 30 to extend to theiroriginal length as the coiled spring 37 pushes the push block 22 awayfrom the vial 80. The chamber 12 can then be refilled if desired withadditional drug to be injected into another body.

The device 10 of FIG. 1A or 5A can be used as a single-use device or formultiple uses. When used as a multiuse device, the cycle time betweenuses can be 0.5 seconds or less.

For example, there is shown in FIG. 10 the device 10 of FIG. 1A coupledto a reservoir 100 that supplies the chamber 12 with a sufficient amountof drug, D, for each injection, and holds enough drug for approximately20 to 200 or more injections. Alternatively, individual doses may beprovided in a plurality of reservoirs sequentially coupled to thedelivery device 10. A valve 102 is associated with a tube 103 connectingthe reservoir 100 with an inlet port 104 of the chamber 12. The valve102 is opened and closed under the direction of the controller 50, or anadditional controller, to allow the desired amount of drug into thechamber 12 for each injection. The device 10 of FIG. 6A can also becoupled to a similar reservoir that is operated in the manner justdescribed.

When the device 10 of FIG. 10 is in use, the controller 50 instructs thevalve 102 to open to allow the drug to flow from the reservoir 100through the inlet port 104 into the chamber 12, and, after a prescribedperiod of time, the controller 50 directs the valve 102 to close so thata desired amount of the drug is held in the chamber 12 for a singleinjection.

Next, or while the chamber 12 is being filled with drug, the operatorpositions the applicator to place the surface 60 of the head 17 againstthe skin, S, of the body. Meanwhile, the capacitor bank 54 is energizedas described above. The operator then triggers the device 10 through thecontroller 50 to discharge the capacitor bank 54, thereby applying apotential across the wires 30 which causes them to contract. As thewires 30 contract, they pull the push block 22 which pushes the piston18 towards the head 17 to force the drug, D, from the chamber 12 throughthe orifice 14 into the body. After the energy in the capacitor bank isdepleted, the potential across the wires 30 is removed which causes thewires 30 to extend to their original length as the coiled spring 37pushes the push block 22 away from the head 17. The controller 50 theninstructs the valve 102 to open to refill the chamber 12 with additionaldrug from the reservoir 100 to be injected into another body.

When the device 10 is intended for multiple uses, it may be desirable toprovide some type of protective sterile barrier between the head 17 andthe skin of the body to eliminate or at least minimize exposing asubsequent body with contaminants from a previous body.

For example, there is shown in FIG. 11 the device 10 provided with asupply of ribbon from a supply roller 110 mounted to the device 10 witha support 112. A sheet of ribbon 111 passes between the face 60 (see,e.g., FIG. 1A) and the skin, S, of the body. After use, the ribbon 111is spooled onto a take-up roller 114 that is mounted to the device 10with a support 116. The ribbon 111 is wide enough to cover the face 60such that none of the face 60 makes contact with the skin, S. The ribbon111 is made of any suitable material that prevents cross-contaminationbetween biological bodies, such as a non-porous flexible material.

The operation of the take-up roller 114, and, optionally, the supplyroller 110, can be controlled by the controller 50, or an additionalcontroller. Thus, when in use, the device 10 ejects drug from theorifice 14 through the ribbon 111 into the body. After the drug has beeninjected into the body, additional drug can be supplied from thereservoir 100 according to the techniques described above, while thecontroller 50 instructs the roller 114 to take up a sufficient amount ofribbon 111 in the direction A, so that the next body is exposed only toa new sterile portion of the ribbon 111 during the injection procedure.

In other implementations, a new sterile head 17 is positioned on thedevice 10 after an injection, while the previous head 17 is disposed ina suitable manner.

Referring now to FIGS. 12A and 12B, there is shown another embodiment ofthe device 10 suitable for multiuse operations. The device 10 isprovided with a series of vials 80 connected together, for example, witha flexible web 120. Enlarged regions 122 and 124 (see, e.g., FIG. 7A) ofthe vials 80 engage with a slot 126 of the base portion 70. Thus, aftereach injection, a driver 200, separate from or integral with the device10, pulls the web 120, and hence the vials 80, in the direction 13 untila vial filled with drug and fed from the top of the base 70 is suitablycoupled with the piston 18 for the next injection. The injectionprocedure proceeds as described earlier, for example, for the embodimentof FIG. 6A. As such, the device 10 can be used in a “machine-gun” likemanner, with new vials being fed through the top of the base 70, whiledepleted vials are pulled out from the bottom of the base 70. The driver200 can be under the control of the controller 50 or another controller.The vials 80 could be fed and removed from the side of the base portion70. Moreover, such an automated arrangement could be implemented withthe device 10 of FIGS. 1-4.

In some implementations, the controller 50 is coupled with a sensor thatdetects skin properties. This information can be used to servo-controlthe actuator 28 to tailor the injection pressure, and, therefore, thedepth of penetration of drug into the skin for a particular application.For instance, when the device 10 is used on a baby, the sensor detectsthe softness of the baby's skin, and the controller 50 uses theproperties of the baby's skin and consequently reduces the injectionpressure. The injection pressure can be adjusted, for example bycontrolling the current amplitude applied to the wires 30 and/or thecurrent pulse rise time and/or duration. When used on an adult orsomeone with sun damaged skin, the controller may increase the injectionpressure. The injection pressure may be adjusted depending on locationof the skin on the body, for example, the face versus the arm of thepatient. The injection pressure can also be tailored to deliver the drugjust underneath the skin or deep into muscle tissue. Moreover, theinjection pressure may be varied over time. For instance, in someimplementations, a large injection pressure is initially used to piercethe skin with the drug, and then a lower injection pressure is used todeliver the drug. A larger injection may also be used to break a sealthat seals the chamber or vial.

Skin is a non-linear, viscoelastic material. Microscopic changes incellular mechanical properties or adhesion between tissue can beobserved as macroscopic changes in static or dynamic mechanical tissueproperties. These factors combine to determine the behavior of skin inresponse to outside stimulants. For small force perturbations about anapplied static force, the skin mechanical dynamics can be approximatedas a linear mechanical system relating the applied force F(t) to skindeformation x(t) as:

$\begin{matrix}{{{F(t)} = {{I\frac{^{2}{x(t)}}{t^{2}}} + {B\frac{{x(t)}}{t}} + {{Kx}(t)}}},} & (1)\end{matrix}$

where I is the inertia in kg, B is the viscosity in kg/s, and K is thestiffness in N/m of skin. After taking the Laplace transform of equation(1), the equivalent transfer function representing the mechanicalcompliance of the skin as a function of frequency, ÿ, is:

$\begin{matrix}{{\frac{x(\omega)}{F(\omega)} = \frac{G\; \omega_{n}^{2}}{\omega^{2} + {2{ϛ\omega}_{n}\omega} + \omega_{n}^{2}}},{where}} & (2) \\{{G = \frac{1}{K}},} & (3) \\{{\omega_{n} = \sqrt{\frac{K}{I}}},{and}} & (4) \\{ϛ = {\frac{1}{2}{\frac{B}{\sqrt{IK}}.}}} & (5)\end{matrix}$

A Bode plot (gain vs. freq.) can be obtained for the above mechanicalsystem, illustrating a decrease in compliance with increase skinstiffness. A tailored stochastic sequence can also be performed bytuning F(t) to pull out the relevant parameters. As such, skinproperties can be determined with system identification techniques. Suchtechniques are described in the article “The Identification of NonlinearBiological Systems: Volterra Kernel Approaches,” by Michael J. Korenbergand Ian W. Hunter, Annals of Biomedical Engineering, Vol. 24 pp.250-269, 1996, the entire contents of which are incorporated herein byreference.

Referring now to FIG. 13, there is shown a skin property sensor 200associated with the drug delivery device 10. The sensor 200 includes anelectromagnetically driven voice coil 202 coupled to a force transducer206 with a flexure 204. The force transducer 206 in turn is coupled to alinear variable differential transducer (LVDT) 208 with a sensor tip201. In the implementation shown, the voice coil 202, the forcetransducer 206, and the LVDT 208 are connected to a controller such asthe controller 50, which drives the sensor 200 as well as receivessignals from the sensor 200. The sensor 200 can be integrated with thedevice 10, or it can be a separate unit. As shown, the sensor ispositioned within the device 10, with the sensor tip 201 located nearthe orifice 14 (see also FIGS. 1A, 5A, and 6A).

Accordingly, when the device 10 is used with the sensor 200, the device10 is initially placed against the skin, S, of the body such that thesensor tip 201 also rests against the skin. The controller 50 thendrives the voice coil 202, for example, up to 20 kHz, to perturb theskin, while the force transducer 202 detects the force the tip 201applies to the skin, and the LVDT 208 detects the displacement of theskin. This data is fed back to the controller 50 which then evaluatesthe skin properties with the system identification techniques describedearlier. Based on the detected skin properties, the controller 50directs the actuator 28 to eject the drug, D, contained in the chamber12, through the orifice 14 with the desired injection pressure.Alternatively, a body portion 210 in which the chamber 12 is defined canfunction as the sensor tip 201. In such implementations, the bodyportion 210 would be coupled to the LVDT 208 and force sensor 206 sothat the chamber 12, body portion 210, and sensor 200 would bepositioned in line.

Other skin property sensor arrangements can also be used with the device10, such as the sensor configuration 300 shown as a block diagram inFIG. 14. The sensor 300 includes a linear electromagnetic actuator 302(e.g., model no. 4910, available from Bruel and Kjaer) verticallymounted to a rigid frame. A strain gauge type load cell 304 (e.g., modelno. ELF-TC13-15, available from Entran, of Fairfield, N.J.) is mountedto the actuator platform for the purpose of measuring the DC offset ofthe system corresponding to the static loading, as measured with amultimeter 303 (e.g., model no. HP 972A, available from Hewlett Packard,or Palo Alto, Calif.) via a signal conditioning amplifier 305. Below theload cell 304 is an impedance head 306 (Bruel and Kjaer model no. 8001)consisting of a piezoelectric accelerometer 306 a and a piezoelectricforce transducer 306 b. The two outputs from the accelerometer recordthe force applied to the skin and its resulting acceleration. Two chargeamplifiers 308′, 308″ (generally 308) (Bruel and Kjaer model no. 2635)transform the force to a proportional voltage and doubly integrate theacceleration to give the skin displacement. The actuator 302 is drivenby an algorithm, such as a Visual BASIC program, that simulates aDynamic Signal Analyzer through a power amplifier 310. The algorithmoutputs a swept sinusoidal signal within a range of pre-determinedfrequencies. This modulation is a small perturbation on top of aninitial static load, which is determined from the output voltage of theload cell 304. The measured force and displacement of the actuator arethen input to two separate channels of a data acquisition board 312 andused to calculate the compliance transfer function gain and phase with acomputer or the controller 50. In one implementation, there is a 50 kHzper channel of the data acquisition board, which can be increased to 100kHz per channel when multiplexed. The A/D is 18 bits with ±4.5 V, whilethe D/A is 18 bits with ±3.0 V. Like that shown in FIG. 13 for thesensor 200, the sensor 300 is preferably associated with the device 10through the controller 50. Accordingly, properties of the skin areanalyzed by the controller 50 based on the data from the sensor 300. Thecontroller 50 then directs the device 10 to eject drug into the bodywith the appropriate injection pressure.

Although the sensors 200 and 300 are shown in combination with thedevice 10, the sensors can be combined with other types of medicaldevices. For example, the sensor can be combined with other types ofneedleless injectors such as those using magnetic, chemical, hydraulic,and spring actuators, and those described in U.S. application Ser. No.10/200,574 filed Jul. 19, 2002, and U.S. Provisional Application No.60/409,090 filed Sep. 6, 2002, incorporated by reference in theirentireties. Additionally, the sensor can be combined with injectors thatuse needles, such as microneedle injectors, and those described in U.S.application Ser. Nos. 10/238,844 filed Sep. 9, 2002 and 10/278,049 filedOct. 21, 2002, also incorporated by reference in their entireties.Advantageously, the sensed properties can be used to control the depthand/or insertion force of the needles.

Furthermore, the sensors 200, 300 can be used to measure skin propertiesof a subject, as described above, or they can be used, to measureproperties of other body surfaces. For example, the sensor can be usedto measure properties of the internal anatomy of subject, such as thesurface of an internal cavity or organ during a surgical procedure.

In some embodiments, the sensors 200 and 300 can be configured as standalone units. Thus, the system components discussed in relation to FIGS.13 and 14 can be packaged within a single housing. The housing can betethered to an external power source, or can include an internal powersource, such as a battery. Additionally, a stand alone unit can beconfigured as a wearable device that can attach to a patient's bodyusing a bandage, or an adhesive. For example, a small force transducerand an accelerometer can be packaged in an adhesive bandage that isplaced on the skin. The transducer first resonates at a resonantfrequency (e.g., 50 Hz) for a period of time (e.g., several seconds).The transducer stimulates the local skin and the accelerometer detectsthe displacement of the skin. A controller can then record the resultingskin displacement in a memory and calculate the compliance gain of theskin. The controller can further determine the mechanical behavior ofthe skin (e.g., stiffness) using the calculated compliance gain. Stillfurther, the controller can further identify the type of skin using itscalculated mechanical behavior and/or compliance gain (e.g., that of ababy or of an adult). The sensor can ultimately generate a signal orcommand used as an indicator to an operator and/or a control signal to amedical device.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. For example, contractile polymers,or any other suitable contracting material, can be used instead of theshape memory alloy. The device 10 may include multiple chambers or mayaccommodate multiple drug vials. Thus, the device 10 is able to deliverdrug sequentially or simultaneously. For example, the device 10 is ableto deliver two or more drugs at once to the body.

1. A medical device comprising: a sensor configured to measure aproperty of an outer layer of an anatomical body surface, the sensorincluding: a source probe configured stimulate a local surface of theouter layer of an anatomical body surface, a detector configured tomeasure a response of the outer layer resulting from the source probe tostimulation; and a controller coupled to the sensor, wherein thecontroller drives the source probe using a tailored stochastic sequenceand determines the property of the outer layer using the measuredresponse received from the detector.
 2. The device of claim 1 whereinthe properties are determined with system identification techniques. 3.The device of claim 2 wherein the body surface is modeled as a secondorder mechanical system.
 4. The device of claim 1 wherein the bodysurface is an internal body surface.
 5. The device of claim 1 whereinthe body surface is the skin of a subject.
 6. The device of claim 1further comprising a servo-controller coupled to a delivery device fordelivering a pharmaceutical, the servo-controller adjusting the deliverycharacteristics of the delivery device based on the surface properties.7. The device of claim 1 wherein the source probe comprises a voicecoil.
 8. The device of claim 1 wherein the detector comprises anaccelerometer detecting displacement of the body surface.
 9. The deviceof claim 1 wherein the detector comprises an linear differentialvariable transducer detecting displacement of the body surface.
 10. Thedevice of claim 9 wherein the detector further comprises a strain gaugemeasuring a static displacement of the body surface.
 11. The device ofclaim 1 further comprising a drug injection device coupled to thesensor, the drug injection device injecting a drug into an anatomicalbody in response to the determined property of the outer layer.
 12. Thedevice of claim 1 wherein the drug injection device comprises aneedleless injector.
 13. A method for measuring properties of an outerlayer of an anatomical body comprising: placing a sensor against anouter layer of an anatomical body; stimulating the outer layer of ananatomical body with the sensor using a tailored stochastic sequence;measuring a response of the outer layer of an anatomical body to thestimulation; and determining a property of the outer layer of ananatomical body based on the measured response to the tailoredstochastic sequence stimulation.
 14. The method of claim 13 whereindetermining a property further comprises using system identificationtechniques.
 15. The method of claim 14 further comprising modeling theouter layer of an anatomical body as a second order mechanical system.16. The method of claim 13 further comprising adjusting the deliveryprofile of a delivery device for delivering a pharmaceutical.
 17. Themethod of claim 16 wherein the delivery device is a drug injectiondevice.
 18. The method of claim 17 wherein the drug injection device isa needleless injection device.
 19. The method of claim 16 wherein theadjusting is performed with a servo-controller based on the determinedproperty.
 20. The method of claim 16 wherein stimulating the outer layerof an anatomical body comprises placing a voice coil against the outerlayer and driving the voice coil at a frequency.
 21. The method of claim16 wherein measuring a response of the outer layer of an anatomical bodyto the stimulation comprises measuring displacement of the outer layer.22. An apparatus for injecting drug into a biological body comprising. adrug injector for holding the drug to be delivered to the body; a skinsensor that measures skin properties of the body; and a servo-controllercoupled to the drug injector and the skin sensor, the servo-controlleradjusting the injection pressure of the drug injector to selectivelydeliver the drug to the body based on the skin properties.
 23. Theapparatus of claim 22 wherein the skin sensor measures the properties ofthe body using a tailored stochastic sequence.
 24. A method forinjecting drug into a biological body comprising: holding a drug to bedelivered to the body in a drug injector; measuring skin properties ofthe body; adjusting the injection pressure of the drug injector with aservo-controller based on the skin properties; and injecting the druginto the body.
 25. The apparatus of claim 24 wherein the skin sensormeasures the properties of the body using a tailored stochasticsequence.